Linking the gut microbiome to host DNA methylation by a discovery and replication epigenome-wide association study

Ayşe Demirkan; Jenny van Dongen; Casey T Finnicum; Harm-Jan Westra; Soesma Jankipersadsing; Gonneke Willemsen; Richard G Ijzerman; Dorret I Boomsma; Erik A Ehli; Marc Jan Bonder; Jingyuan Fu; Lude Franke; Cisca Wijmenga; Eco J C de Geus; Alexander Kurilshikov; Alexandra Zhernakova

doi:10.1186/s12864-024-11136-x

Linking the gut microbiome to host DNA methylation by a discovery and replication epigenome-wide association study

BMC Genomics. 2024 Dec 19;25(1):1224. doi: 10.1186/s12864-024-11136-x.

Authors

Ayşe Demirkan^{1

2}, Jenny van Dongen^{3

4}, Casey T Finnicum⁵, Harm-Jan Westra⁶, Soesma Jankipersadsing⁶, Gonneke Willemsen^{3

4}, Richard G Ijzerman⁷, Dorret I Boomsma^{4

8}, Erik A Ehli⁵, Marc Jan Bonder⁶, Jingyuan Fu^{6

9}, Lude Franke⁶, Cisca Wijmenga⁶, Eco J C de Geus^{3

4}, Alexander Kurilshikov⁶, Alexandra Zhernakova¹⁰

Affiliations

¹ Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. [email protected].
² Department of Clinical and Experimental Medicine, Section of Statistical Multi-omics, School of Biosciences and Medicine & People-Centered AI institute University of Surrey, Guildford, United Kingdom. [email protected].
³ Biological Psychology, Vrije Universiteit, Amsterdam, the Netherlands.
⁴ Amsterdam Public Health Research Institute, Amsterdam MC, Amsterdam, the Netherlands.
⁵ Avera Institute of Human Genetics, Avera McKennan Hospital & University Health Center, Sioux Falls, Sioux Falls, SD, USA.
⁶ Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
⁷ Department of Endocrinology, Amsterdam University Medical Center, location AMC, Amsterdam, the Netherlands.
⁸ Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
⁹ Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
¹⁰ Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. [email protected].

Abstract

Microbiome influences multiple human systems, but its effects on gene methylation is unknown. We investigated the relations between gene methylation in blood and the abundance of common gut bacteria profiled by 16s rRNA gene sequencing in two population-based Dutch cohorts: LifeLines-Deep (LLD, n = 616, discovery) and the Netherlands Twin Register (NTR, n = 296, replication). In LLD, we also explored microbial pathways using data generated by shotgun metagenomic sequencing (n = 683). Methylation in both cohorts was profiled in blood samples using the Illumina 450K array. Discovery and replication analysis identified two independent CpGs associated with the genus Eggerthella: cg16586104 (P_{meta-analysis} = 3.21 × 10^-11) and cg12234533 (P_{meta-analysis} = 4.29 × 10^-10). We also show that microbiome can mediate the effect of environmental factors on host gene methylation. In this first association study linking epigenome to microbiome, we found and replicated the associations of two CpGs to the abundance of genus Eggerthella and identified microbiome as a mediator of the exposome. These associations are observational and suggest further investigation in larger and longitudinal set-ups.

Keywords: 16s rRNA; DNA methylation; Gut microbiome; Host gene methylation; Shotgun-metagenomics.

MeSH terms

Adult
CpG Islands / genetics
DNA Methylation*
Epigenome*
Female
Gastrointestinal Microbiome* / genetics
Genome-Wide Association Study*
Humans
Male
Middle Aged
Netherlands
RNA, Ribosomal, 16S / genetics

Substances

RNA, Ribosomal, 16S